Lysophosphatidic acid acyltransferase (LPAAT) catalyzes the acylation of lysophosphatidic acid (LPA) to phosphatidic acid. LPA is the simplest glycerophospholipid, consisting of a glycerol molecule, a phosphate group, and a mono-saturated fatty acyl chain. LPAAT adds a second fatty acyl chain to LPA, producing phosphatidic acid (PA). PA is the precursor molecule for diacylglycerols, which are necessary for the production of phospholipids, and for triacylglycerols, which are essential biological fuel molecules.
In addition to being a crucial precursor molecule in biosynthetic reactions, LPA has recently been added to the list of intercellular lipid messenger molecules. LPA interacts with G protein-coupled receptors, coupling to various independent effector pathways including inhibition of adenylate cyclase, stimulation of phospholipase C, activation of MAP kinases, and activation of the small GTP-binding proteins Ras and Rho. (Moolenaar, W. H. (1995) J. Biol. Chem 28-:12949-12952.) The physiological effects of LPA have not been fully characterized yet, but they include promoting growth and invasion of tumor cells. Addition of LPA to ovarian or breast cancer cell lines induced cell proliferation, increased intracellular calcium levels, and activated MAP kinase. (Xu, Y et al. (1995) Biochem. J. 309:933-940.) In addition, LPA induced MM1 tumor cells to invade cultured mesothelial cell monolayers. (Imamura, F. et al. (1993) Biochem. Biophys. Res. Comm. 193:497-503.)
Phosphatidic acid (PA), the product of LPAAT, is also a messenger molecule.
is a key messenger in a common signaling pathway activated by proinflammatory mediators such as interleukin-1.beta., tumor necrosis factor .alpha., platelet activating factor, and lipid A. (Bursten, S. L. et al. (1992) Am. J. Physiol. 262:C328-C338; Bursten S. L. et al. (1991) J. Biol. Chem. 255:20732-20743; Kester, M. (1993) J. Cell Physiol. 156:317-325.) For example, in a mouse model of inflammatory response, inhibition of LPAAT reduced lipopolysaccharide-mediated endotoxic shock. (Abraham, E. et al. (1995) J. Exp. Med. 181:569-575; Rice, G. C. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3857-3861.) Thus, LPAAT activity may mediate inflammatory responses to various proinflammatory agents.
The discovery of a new human lysophosphatidic acid acyltranferase and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of cancer and autoimnmune disorders.